Growth factors are substances that induce cell proliferation, typically by binding to specific receptors on cell surfaces. One such growth factor is epidermal growth factor (EGF). EGF induces proliferation of a variety of cells in vivo, and is required for the growth of most cultured cells.
The EGF receptor is a 170-180 kD membrane-spanning glycoprotein, which is detectable on a wide variety of cell types. The extracellular N-terminal domain of the receptor is highly glycosylated and binds EGF. The cytoplasmic C-terminal domain of the receptor contains an EGF-dependent tyrosine-specific protein kinase that is capable of both autophosphorylation and the phosphorylation of other protein substrates. The two domains are connected by a single 21 amino acid hydrophobic transmembrane region. The binding of EGF to its receptor activates the receptor tyrosine kinase, which phosphorylates a variety of cellular proteins (including the EGF receptor itself). This phosphorylation initiates a signal transduction pathway that ultimately leads to DNA replication, RNA and protein synthesis, and cell division. EGF also induces the concentration of the receptor into clathrin-coated pits, internalization into intracellular vesicles, and finally degradation in the lysosomes.
The amplification or overexpression of the EGF receptor is associated with the uncontrolled cell division of many cancers. Published studies support a role for the EGF receptor in cell transformation and maintenance of the transformed phenotype. There is also a high level of sequence homology between the EGF receptor and the avian v-erbB oncogene product. In addition, overexpression of the EGF receptor has been shown to result in the EGF-dependent transformation of NIH 3T3 cells.
Many tumors of mesodermal and ectodermal origin overexpress the EGF receptor. For example, the EGF receptor has been shown to be overexpressed in many gliomas, squamous cell carcinomas, breast carcinomas, melanomas, invasive bladder carcinomas and esophageal cancers. In addition, studies with primary human mammary tumors have shown a correlation between high EGF receptor expression and the presence of metastases, higher rates of proliferation, and shorter patient survival.
Attempts to exploit the EGF receptor system for anti-tumor therapy have generally involved the use of monoclonal antibodies against the EGF receptor. However, this approach has serious drawbacks. The monoclonal antibodies developed to date are effective inhibitors of cell growth in only some of the existing cancer cell lines. In addition, studies with athymic mouse xenografts suggest that therapeutic intervention with anti-receptor antibodies will require prolonged exposure, which may result in the generation of antibodies against the anti-receptor antibodies in the patient. Thus, to date, no successful anti-tumor therapies exploiting the EGF receptor system have been developed.
Accordingly, there is a need in the art for improved compounds and methods for treating EGF-receptor associated cancers. The present invention fulfills this need and provides further related advantages.